This is a 371 of PCT/KR99/00421, filed Aug. 2, 1999.
1. Field of the Invention
The present invention relates to the use of the lipoxygenase metabolites of arachidonic acid and their derivatives as capsaicin-channel or -receptor agonists. More particularly, the present invention relates to the metabolites produced from arachidonic acid by the catalytic action of lipoxygenase, which can be used as an analgesic which is superior in pain-relieving efficacy and free of durg resistance and addition.
2. Description of the Prior Art
Analgesics developed thus far are largely classified into two categories: narcotic and antiphlogistic. The former, exerting its pharmacological effects on the central nervous system, shows potent pain-alleviating activity with accompaniments of strong side effects including resistance and addiction. With an unclear explanation regarding their pharmaceutical mechanism, antiphlogistic analgesics are weaker in pain relief than narcotic analgesics as well as may cause gastric and liver troubles (Insel, 1996; Reisine and Pasternak, 1996).
Referring to FIG. 1, there is illustrated a pain transmission mechanism. When pain from a peripheral organ stimulates a sensory nerve cell, the cell generates a nerve impulse which is then transmitted to the spinal cord in which the nerve impulse is propagated along neurons to many nuclei in the brain. Ultimately, the nerve impulse is transmitted into the pain sensory center of the brain, making the body feel pain (Wills and Coggeshal, 1991; Yaksh, 1986).
Peppers, in both the Orient and the Occident, are used as a spice to provide foods with a hot taste. It is capsaicin(;CAP) that provides the hot taste of pepper. Particularly, CAP is known to be closely related to pain. In the early stages of stimulation, CAP exists sensory nerves, causing serious pain. However, if accumulation of CAP prolongs, there occurs desensitization, leading to an analgesic effect which lasts for a long period of time (Holzer P, Pharmacol Rev. 43:143-201, 1991). In addition, CAP may reportedly serve as a kind of neurotoxin, which allows sensory neurons a conformational change, leading sensory neurons to being permanently damaged (Holzer P, supra; Szallasi and Blumberg, Adv. Pharmacol. 24:123-155, 1993). Recently, active research has been directed to the development of CAP derivatives to potent analgesics, making use of the pain-relieving effect due to the desensitization of CAP (Szallasi and Blumberg, 1996; Rouhi, 1998). Because the neurotoxic effect of CAP is confined only to small sensory neurons, advantage is believed to be taken of CAP to develop addiction-free analgesics which exert their pharmacological actions on the peripheral neuron system, but not on the central nerve system.
The present inventors found a non-selective cation channel which opens when being directly associated with CAP, so as to mediate the neural excitation induced by CAP. This mechanism is schematically depicted in FIG. 2. Up to recent years, it has been known that a whole-cell current is caused by CAP, but single-channel currents which can conduct the whole-cell current response have clearly been revealed. The present inventors found a non-selective cation channel which can be activated by CAP depending on the concentration of CAP and reported that this channel is activated specifically by CAP and inhibited by capsazepine (;CZP), a CAP-receptor antagonist (Oh, et al., 1996).
Also, it was reported that the CAP channel is non-selectively permeable to cations, such as Na+, Ca2+, etc., to depolarize the sensory nerve cells (Oh, et al., supra). When CAP is added to the extracellular side of the cell membrane of sensory nerve cells, the CAP channel is activated without the aid of a second messenger, which indicates that the CAP channel is a ligand-gated ion channel (Oh, et al., supra).
The fact that CAP channels, which can be activated by CAP, an exogenous material, exist in sensory nerve cells suggests that there be any endogenous material that can activate the CAP channels. In addition, the research result that shows the reduction of inflammatory pain by CZP, a CAP-receptor antagonist (Kwak, et al., 1998), enables the present inventors to expect that, upon inflammation, endogenous CAP-like substances occur and bind to the CAP channels to activate them, thereby causing pain. Further, because CAP binds to the intracellular side of the CAP channel (Oh, et al., 1996b), the endogenous CAP-like substances are expected to be synthesized within cells.
CAP channels, which play an essential role in causing pain, exist, in abundance, in sensory neurons. When they are, for instance, activated by CAP, the opening of CAP channels causes a strong pain and then the desensitization of the channel shows an analgesic effect. Hence, the endogenous active substances which exert an action on the CAP channels are absolutely possible to use as novel analgesics which can overcome the problems that conventional analgesics have, such as the tolerance and addition of narcotic analgesics and the weak efficacy of antiphlogistic analgesics. Moreover, the substances, if existing, are expectedly almost free of side effects because they are originated from cells. Therefore, if an endogenous active substance, such as a ligand, for CAP channels had been revealed, the substance itself would have been an excellent analgesic as well as served as a model for the development of its analogue compounds which can be used as analgesics with a new concept.
Many researchers have made efforts to find endogenous ligands for CAP channels, but did not succeed in the research in this microscopic world.
The inventor found that metabolic products of lipoxygenase(;LO) activate the CAP channel. The inventor also found that among products of LO, 12-hydroxyeicosatetraenoic acid (12-HPETE) is the most potent and that the two materials are structurally similar.
Knowledge of the pain generation mechanism in sensory nerves allows the development of analgesics which can relieve pain, leading to the present invention.
It is therefore an object of the present invention to overcome the above problems encountered in prior arts and to provide an analgesic which has superior pain-relieving efficacy and lacks drug resistance and addiction properties.
Based on the present invention, the above object could be accomplished by a provision of the use lipoxygenase metabolites of arachidonic acid as a capsaicin-channel or-receptor agonists.